The goal of this proposal is to gain an improved understanding at the molecular and cellular level of the human form of the MHC Class I-related receptor, FcRn. Recent data suggest that in addition to being the receptor that transports maternal immunoglobulin G (IgG) from mother to young, FcRn regulates the serum levels of IgG. IgG homeostasis is most likely maintained by FcRn expression in endothelial cells of the microvasculature. FcRn is also expressed in epithelial cells at diverse body sites (e.g. intestine, kidney and lung). FcRn transports IgG within (recycling) and across (transcytosis) cells, and is a protective receptor which salvages IgG from lysosomal degradation. Although human FcRn (hFcRn) and mouse FcRn (mFcRn) share about 65% amino acid identity, recent studies indicate that there are significant differences in IgG binding specificity. Intracellular trafficking studies of hFcRn and rat FcRn (highly homologous to mFcRn) suggest that there may also be variations at this level. As a result, studies in mice may not always be reliable indicators of hFcRn function. The current study is directed towards better understanding the similarities and differences between human and mouse FcRn. In turn, this should lead to improved knowledge of hFcRn. Our specific aims are: 1)To understand the molecular basis of the distinct binding specificity of hFcRn. 2) To assess the effects of IgG mutations on functional activity in mouse and human systems. 3) To analyze the intracellular trafficking of hFcRn in endothelial cells. Our studies are therefore directed towards addressing the fundamental question as to how hFcRn functions to maintain serum IgG levels, with a particular focus on hFcRn-lgG interactions and hFcRn trafficking in endothelial cells. This impacts the successful application of therapeutic and prophylactic IgGs, and also has broader relevance to the factors that regulate humoral immunity.